tbuckley/cabot-search huggingface dataset:
Immune tolerance against infused FVIII in hemophilia A is mediated by PD-L1+ Tregs
Authors: Janine Becker-Gotot, Mirjam Meissner, Vadim Kotov, Blanca Jurado-Mestre, Andrea Maione, Andreas Pannek, Thilo Albert, Chrystel Flores, Frank A. Schildberg, Paul A. Gleeson, Birgit M. Reipert, Johannes Oldenburg, Christian Kurts
Journal: Journal of Clinical Investigation (2022)

A major complication of hemophilia A therapy is the development of alloantibodies (inhibitors) that neutralize intravenously administered coagulation factor VIII (FVIII). Immune tolerance induction therapy (ITI) by repetitive FVIII injection can eradicate inhibitors, and thereby reduce morbidity and treatment costs. However, ITI success is difficult to predict and the underlying immunological mechanisms are unknown. Here, we demonstrated that immune tolerance against FVIII under nonhemophilic conditions was maintained by programmed death (PD) ligand 1-expressing (PD-L1-expressing) regulatory T cells (Tregs) that ligated PD-1 on FVIII-specific B cells, causing them to undergo apoptosis. FVIII-deficient mice injected with FVIII lacked such Tregs and developed inhibitors. Using an ITI mouse model, we found that repetitive FVIII injection induced FVIII-specific PD-L1+ Tregs and reengaged removal of inhibitor-forming B cells. We also demonstrated the existence of FVIII-specific Tregs in humans and showed that such Tregs upregulated PD-L1 in patients with hemophilia after successful ITI. Simultaneously, FVIII-specific B cells upregulated PD-1 and became killable by Tregs. In summary, we showed that PD-1-mediated B cell tolerance against FVIII operated in healthy individuals and in patients with hemophilia A without inhibitors, and that ITI reengaged this mechanism. These findings may impact monitoring of ITI success and treatment of patients with hemophilia A.
Mortality Risk Among Patients Hospitalized Primarily for COVID-19 During the Omicron and Delta Variant Pandemic Periods — United States, April 2020–June 2022
Authors: Stacey Adjei, Kai Hong, Noelle-Angelique M. Molinari, Lara Bull-Otterson, Umed A. Ajani, Adi V. Gundlapalli, Aaron M. Harris, Joy Hsu, Sameer S. Kadri, Jon Starnes, Kristin Yeoman, Tegan K. Boehmer
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

The risk for COVID-19-associated mortality increases with age, disability, and underlying medical conditions (1). Early in the emergence of the Omicron variant of SARS-CoV-2, the virus that causes COVID-19, mortality among hospitalized COVID-19 patients was lower than that during previous pandemic peaks (2-5), and some health authorities reported that a substantial proportion of COVID-19 hospitalizations were not primarily for COVID-19-related illness,* which might account for the lower mortality among hospitalized patients. Using a large hospital administrative database, CDC assessed in-hospital mortality risk overall and by demographic and clinical characteristics during the Delta (July-October 2021), early Omicron (January-March 2022), and later Omicron (April-June 2022) variant periods† among patients hospitalized primarily for COVID-19. Model-estimated adjusted mortality risk differences (aMRDs) (measures of absolute risk) and adjusted mortality risk ratios (aMRRs) (measures of relative risk) for in-hospital death were calculated comparing the early and later Omicron periods with the Delta period. Crude mortality risk (cMR) (deaths per 100 patients hospitalized primarily for COVID-19) was lower during the early Omicron (13.1) and later Omicron (4.9) periods than during the Delta (15.1) period (p<0.001). Adjusted mortality risk was lower during the Omicron periods than during the Delta period for patients aged ≥18 years, males and females, all racial and ethnic groups, persons with and without disabilities, and those with one or more underlying medical conditions, as indicated by significant aMRDs and aMRRs (p<0.05). During the later Omicron period, 81.9% of in-hospital deaths occurred among adults aged ≥65 years and 73.4% occurred among persons with three or more underlying medical conditions. Vaccination, early treatment, and appropriate nonpharmaceutical interventions remain important public health priorities for preventing COVID-19 deaths, especially among persons most at risk.
Management of Patients at Risk for and With Left Ventricular Thrombus: A Scientific Statement From the American Heart Association
Authors: Glenn N. Levine, John W. McEvoy, James C. Fang, Chinwe Ibeh, Cian P. McCarthy, Arunima Misra, Zubair I. Shah, Chetan Shenoy, Sarah A. Spinler, Srikanth Vallurupalli, Gregory Y.H. Lip
Journal: Circulation (2022)

Despite the many advances in cardiovascular medicine, decisions concerning the diagnosis, prevention, and treatment of left ventricular (LV) thrombus often remain challenging. There are only limited organizational guideline recommendations with regard to LV thrombus. Furthermore, management issues in current practice are increasingly complex, including concerns about adding oral anticoagulant therapy to dual antiplatelet therapy, the availability of direct oral anticoagulants as a potential alternative option to traditional vitamin K antagonists, and the use of diagnostic modalities such as cardiac magnetic resonance imaging, which has greater sensitivity for LV thrombus detection than echocardiography. Therefore, this American Heart Association scientific statement was commissioned with the goals of addressing 8 key clinical management questions related to LV thrombus, including the prevention and treatment after myocardial infarction, prevention and treatment in dilated cardiomyopathy, management of mural (laminated) thrombus, imaging of LV thrombus, direct oral anticoagulants as an alternative to warfarin, treatments other than oral anticoagulants for LV thrombus (eg, dual antiplatelet therapy, fibrinolysis, surgical excision), and the approach to persistent LV thrombus despite anticoagulation therapy. Practical management suggestions in the form of text, tables, and flow diagrams based on careful and critical review of actual study data as formulated by this multidisciplinary writing committee are given.
Error in Results
Journal: JAMA Network Open (2022)

Deborah F. Tate, PhD; Lesley D. Lutes, PhD; Maria Bryant, PhD; Kimberly P. Truesdale, PhD; Karen E. Hatley, MPH, RD; Zoe Griffiths, RD; Tricia S. Tang, PhD; Louise D. Padgett; Angela M. Pinto, PhD; June Stevens, PhD; Gary D. Foster, PhD
Subclinical Risk Factors for Heart Failure With Preserved and Reduced Ejection Fraction Among Black Adults
Authors: Li Zhao, Rani Zierath, Jenine E. John, Brian Lee Claggett, Michael E. Hall, Donald Clark, Kenneth R. Butler, Adolfo Correa, Amil M. Shah
Journal: JAMA Network Open (2022)

Sparse data exist regarding the contributions of subclinical impairments in cardiovascular and noncardiovascular function to incident heart failure (HF) with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) among Black US residents, limiting understanding of the etiology of HF subtypes.To identify subclinical cardiovascular and noncardiovascular risk factors associated with HFrEF and HFpEF in Black US residents.This cohort study used cross-sectional and time-to-event analysis with data from the community-based Jackson Heart Study (JHS), a longitudinal cohort study with baseline data collected from 2000 to 2004 (visit 1) and 10-year follow-up for incident HF. Black US residents from the Jackson, Mississippi, metropolitan area enrolled in JHS; those with prevalent HF, with moderate or greater aortic or mitral valve diseases on visit 1, who died before 2005, and who had missing HF status on follow-up were excluded. The analysis included 4361 participants and was performed between June 2020 to August 2021.Quantitative measures of cardiovascular (left ventricular mass index [LVMI], left ventricular ejection fraction [LVEF], left atrial [LA] diameter, and pulse pressure) and noncardiovascular (percent predicted forced expiration volume in 1 second [FEV1 (percent predicted)], estimated glomerular filtration rate (eGFR), waist circumference, and hemoglobin A1c [HbA1c] level) organ function.Incident HF, HFrEF, and HFpEF over 10-year follow-up.The 4361 participants had a mean (SD) age of 54 (13); 2776 (64%) were women; and there were 163 HFpEF and 146 HFrEF events. In multivariable models incorporating measures reflecting each organ system, factors associated with incident HFpEF included greater LA diameter (hazard ratio [HR], 1.23; 95% CI, 1.03-1.47; P = .02), higher pulse pressure (HR, 1.23; 95% CI, 1.05-1.44; P = .009), lower FEV1 (percent predicted) (HR, 1.22; 95% CI, 1.04-1.43; P = .02), lower eGFR (HR, 1.43; 95% CI, 1.19-1.72; P < .001), higher HbA1c level (HR, 1.25; 95% CI, 1.07-1.45; P = .005), and higher waist circumference (HR, 1.41; 95% CI, 1.18-1.69; P < .001). Factors associated with incident HFrEF included greater LVMI (HR, 1.25; 1.07-1.46; P = .005), lower LVEF (HR, 1.65; 95% CI, 1.42-1.91; P < .001), lower FEV1 (percent predicted) (HR, 1.19; 95% CI, 1.00-1.42; P = .047), and lower eGFR (HR, 1.27; 95% CI, 1.04-1.55; P = .02).In this community-based cohort study of Black US residents, subclinical impairments in cardiovascular and noncardiovascular organ function were differentially associated with risk of incident HFpEF and HFrEF.
Expanded Parameters in Active Surveillance for Low-risk Papillary Thyroid Carcinoma
Authors: Allen S. Ho, Sungjin Kim, Cynthia Zalt, Michelle L. Melany, Irene E. Chen, Joan Vasquez, Jon Mallen-St. Clair, Michelle M. Chen, Missael Vasquez, Xuemo Fan, Welmoed K. van Deen, Robert W. Haile, Timothy J. Daskivich, Zachary S. Zumsteg, Glenn D. Braunstein, Wendy L. Sacks
Journal: JAMA Oncology (2022)

Unlike for prostate cancer, active surveillance for thyroid cancer has not achieved wide adoption. The parameters by which this approach is feasible are also not well defined, nor is the effect of patient anxiety.
Comparison of Management and Outcomes in <i>ERBB2</i>-Low vs <i>ERBB2</i>-Zero Metastatic Breast Cancer in France
Authors: Ombline de Calbiac, Amélie Lusque, Audrey Mailliez, Thomas Bachelot, Lionel Uwer, Marie-Ange Mouret-Reynier, George Emile, Christelle Jouannaud, Anthony Gonçalves, Anne Patsouris, Véronique Diéras, Marianne Leheurteur, Thierry Petit, Paul Cottu, Jean-Marc Ferrero, Véronique D'Hondt, Isabelle Desmoulins, Joana Mourato-Ribeiro, Anne-Laure Martin, Jean-Sébastien Frenel
Journal: JAMA Network Open (2022)

Importance ERBB2 -low (ie, ERBB2 immunohistochemistry score of 1+ or 2+ in the absence of ERBB2 gene amplification) breast cancer (BC) is a new entity, with emerging dedicated treatments. Little is known about its prognosis and response to conventional therapy compared with ERBB2 -zero breast tumors (ie, those with an immunohistochemistry score of 0). Objective To compare the outcomes for patients with ERBB2 -low metastatic BC (MBC) with those of patients with ERBB2 -zero MBC. Design, Setting, and Participants This cohort study was conducted from the Epidemiological Strategy and Medical Economics MBC platform and included patients with MBC treated between 2008 and 2016 in 18 French comprehensive cancer centers. The data analysis was conducted from July 16, 2020, to April 1, 2022. Main Outcomes and Measures The main outcome was overall survival (OS), and the secondary outcome was progression-free survival under first-line treatments (PFS1). Results The median (range) age was 60.0 (22.0-103.0) years. Among 15 054 patients with MBC, 4671 (31%) had ERBB2 -low MBC and 10 383 (69%) had ERBB2 -zero MBC. The proportion of ERBB2 -low cancers was higher among patients with hormone receptor–positive MBC than those with hormone receptor–negative disease (4083 patients [33.0%] vs 588 patients [21.0%]). With a median follow-up of 49.5 months (95% CI, 48.6-50.4 months), the median OS of the ERBB2 -low group was 38.0 months (95% CI, 36.4-40.5 months) compared with 33.9 months (95% CI, 32.9-34.9 months) for the ERBB2 -zero group ( P &amp;lt; .001). After adjustment for age, visceral metastases, number of metastatic sites, de novo disease, period of care, and hormone receptor status, patients with ERBB2 -low MBC had slightly better OS compared with patients with ERBB2 -zero MBC (adjusted hazard ratio, 0.95; 95% CI, 0.91-0.99; P = .02). In contrast, PFS1 did not differ by ERBB2 status (adjusted hazard ratio, 0.99; 95% CI, 0.95-1.02; P = .45). No significant differences in OS and PFS1 were observed in multivariate analyses by hormone receptor status and types of frontline treatment. Conclusions and Relevance In this large cohort study, patients with ERBB2 -low MBC had a slightly better OS than those with completely ERBB2 -zero tumors, but identical PFS1, which could help guide treatment selection.
Differences in Patient Outcomes across the Pulmonary Fibrosis Foundation Care Center Network
Authors: Ryan D. Boente, Emily N. White, Caitlin M. Baxter, Jessica E. Shore, Harold R. Collard, Joyce S. Lee, Rodeo Abrencillo, Nitin Bhatt, Ryan Boente, Erica Farrand, Craig Glazer, Tristan Huie, Hyun Kim, Joyce S. Lee, Murali Ramaswamy, Rupal Shah, Jessica Shore, Krishna Thavarajah
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Differences in Patient Outcomes across the Pulmonary Fibrosis Foundation Care Center Network." American Journal of Respiratory and Critical Care Medicine, 207(2), pp. 214–218
Comprehensive and scalable quantification of splicing differences with MntJULiP
Authors: Guangyu Yang, Sarven Sabunciyan, Liliana Florea
Journal: Genome biology (2022)

Tools for differential splicing detection have failed to provide a comprehensive and consistent view of splicing variation. We present MntJULiP, a novel method for comprehensive and accurate quantification of splicing differences between two or more conditions. MntJULiP detects both changes in intron splicing ratios and changes in absolute splicing levels with high accuracy, and can find classes of variation overlooked by other tools. MntJULiP identifies over 29,000 differentially spliced introns in 1398 GTEx brain samples, including 11,242 novel introns discovered in this dataset. Highly scalable, MntJULiP can process thousands of samples within hours to reveal splicing constituents of phenotypic differentiation.
Suicides Among American Indian or Alaska Native Persons — National Violent Death Reporting System, United States, 2015–2020
Authors: Deborah Stone, Eva Trinh, Hong Zhou, Laura Welder, Pamela End of Horn, Katherine Fowler, Asha Ivey-Stephenson
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Compared with the general U.S. population, American Indian or Alaska Native (AI/AN) persons, particularly those who are not Hispanic or Latino (Hispanic) AI/AN, are disproportionately affected by suicide; rates among this group consistently surpass those among all other racial and ethnic groups (1). Suicide rates among non-Hispanic AI/AN persons increased nearly 20% from 2015 (20.0 per 100,000) to 2020 (23.9), compared with a <1% increase among the overall U.S. population (13.3 and 13.5, respectively) (1). Understanding characteristics of suicide among AI/AN persons is critical to developing and implementing effective prevention strategies. A 2018 report described suicides in 18 states among non-Hispanic AI/AN persons only (2). The current study used 2015-2020 National Violent Death Reporting System (NVDRS) data among 49 states, Puerto Rico, and the District of Columbia to examine differences in suicide characteristics and contributing circumstances among Hispanic and non-Hispanic AI/AN populations, including multiracial AI/AN. Results indicated higher odds across a range of circumstances, including 10 of 14 relationship problems (adjusted odds ratio [aOR] range = 1.2-3.8; 95% CI range = 1.0-5.3) and six of seven substance use problems (aOR range = 1.2-2.3; 95% CI range = 1.1-2.5), compared with non-AI/AN persons. Conversely, AI/AN decedents had reduced odds of having any current known mental health condition, any history of mental health or substance use treatment, and other common risk factors (aOR range = 0.6-0.8; 95% CI = 0.2-0.9). Suicide is preventable. Communities can implement a comprehensive public health approach to suicide prevention that addresses long-standing inequities affecting AI/AN populations (3).
Short-term Outcomes of Laparoscopy-Assisted vs Open Surgery for Patients With Low Rectal Cancer
Authors: Wei-Zhong Jiang, Jian-Min Xu, Jia-Di Xing, Hui-Zhong Qiu, Zi-Qiang Wang, Liang Kang, Hai-Jun Deng, Wei-Ping Chen, Qing-Tong Zhang, Xiao-Hui Du, Chun-Kang Yang, Yin-Cong Guo, Ming Zhong, Kai Ye, Jun You, Dong-Bo Xu, Xin-Xiang Li, Zhi-Guo Xiong, Kai-Xiong Tao, Ke-Feng Ding, Wei-Dong Zang, Yong Feng, Zhi-Zhong Pan, Ai-Wen Wu, Feng Huang, Ying Huang, Ye Wei, Xiang-Qian Su, Pan Chi, Guo-Dong He, Zhen-Dan Yao, Yi Xiao, Guo-Le Lin, Chao-Yang Gu, Xiao-Wen He, Ya-Nan Wang, Qi-Ken Li, Rui Guo, Da Teng, Yu-Gang Yang, Shao-Lan Qin, Jian-An Lin, Qing-Qi Hong, Wen-Feng Li, Lei Liang, Jun-Jie Hu, Xing-Hua Liu, Jun Li, Hong Zhang
Journal: JAMA Oncology (2022)

The efficacy of laparoscopic vs open surgery for patients with low rectal cancer has not been established.
Feasibility of a Novel Academic BCMA-CART (HBI0101) for the Treatment of Relapsed and Refractory AL Amyloidosis
Authors: Shlomit Kfir-Erenfeld, Nathalie Asherie, Sigal Grisariu, Batia Avni, Eran Zimran, Miri Assayag, Tatyana Dubnikov Sharon, Marjorie Pick, Eyal Lebel, Adir Shaulov, Yael C. Cohen, Irit Avivi, Cyrille J. Cohen, Polina Stepensky, Moshe E. Gatt
Journal: Clinical Cancer Research (2022)

Abstract Purpose: AL amyloidosis (AL) treatments are generally based on those employed for multiple myeloma. Anti–B-cell maturation antigen (BCMA) chimeric antigen receptor T (CART)-cell therapy, already approved for multiple myeloma, might be too toxic for patients with AL. Experimental Design: Here we describe the ex vivo applicability of a novel in-house, academic anti-BCMA CAR construct on AL primary cells, as well as the safety and efficacy in 4 patients with relapsed/refractory (RR) primary AL, treated in a phase I clinical trial (NCT04720313). Results: Three had MAYO stage IIIa cardiac involvement at enrollment. The treatment proved relatively safe, with a short and manageable grade 3 cytokine release syndrome evident in 2 patients and no neurotoxicity in any. Cardiac decompensations, observed in 2 patients, were also short and manageable. The overall hematologic response and complete response rates were observed in all patients with an organ response evident in all four. Within a median follow-up period of 5.2 (2.5–9.5) months, all 4 patients maintained their responses. Conclusions: BCMA-CART cells provide a first proof-of-concept that this therapy is safe enough and highly efficacious for the treatment of patients with advanced, RR AL.
Error in Results and Table 1
Journal: JAMA Oncology (2022)

Caicun Zhou, PhD, MD; Suresh S. Ramalingam, MD; Tae Min Kim, MD, PhD; Sang-We Kim, MD; James Chih-Hsin Yang, MD; Gregory J. Riely, MD; Tarek Mekhail, MD; Danny Nguyen, MD; Maria R. Garcia Campelo, MD; Enriqueta Felip, MD; Sylvie Vincent, PhD; Shu Jin, MS; Celina Griffin, PharmD; Veronica Bunn, PhD; Jianchang Lin, PhD; Huamao M. Lin, PhD; Minal Mehta, MBBS; Pasi A. Jänne, MD, PhD
The changes of eosinophil counts in patients after treatment of Dupilumab: A systematic review and meta‐analysis
Authors: Boyang Zhou, Surong Liang, Shuai Shang, Lujing Xiang, Linfeng Li
Journal: Allergy (2022)

Figures S1-S6 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Lipid metabolism in pancreatic cancer: emerging roles and potential targets
Authors: Xinpeng Yin, Ruiyuan Xu, Jianlu Song, Rexiati Ruze, Yuan Chen, Chengcheng Wang, Qiang Xu
Journal: Cancer Communications (2022)

Abstract Pancreatic cancer is one of the most serious health issues in developed and developing countries, with a 5‐year overall survival rate currently &lt;9%. Patients typically present with advanced disease due to vague symptoms or lack of screening for early cancer detection. Surgical resection represents the only chance for cure, but treatment options are limited for advanced diseases, such as distant metastatic or locally progressive tumors. Although adjuvant chemotherapy has improved long‐term outcomes in advanced cancer patients, its response rate is low. So, exploring other new treatments is urgent. In recent years, increasing evidence has shown that lipid metabolism can support tumorigenesis and disease progression as well as treatment resistance through enhanced lipid synthesis, storage, and catabolism. Therefore, a better understanding of lipid metabolism networks may provide novel and promising strategies for early diagnosis, prognosis estimation, and targeted therapy for pancreatic cancer patients. In this review, we first enumerate and discuss current knowledge about the advances made in understanding the regulation of lipid metabolism in pancreatic cancer. In addition, we summarize preclinical studies and clinical trials with drugs targeting lipid metabolic systems in pancreatic cancer. Finally, we highlight the challenges and opportunities for targeting lipid metabolism pathways through precision therapies in pancreatic cancer.
Influence of Age on the Diagnosis of Myocardial Infarction
Authors: Matthew T.H. Lowry, Dimitrios Doudesis, Ryan Wereski, Dorien M. Kimenai, Christopher Tuck, Amy V. Ferry, Anda Bularga, Caelan Taggart, Kuan K. Lee, Andrew R. Chapman, Anoop S.V. Shah, David E. Newby, Nicholas L. Mills, Atul Anand
Journal: Circulation (2022)

The 99th centile of cardiac troponin, derived from a healthy reference population, is recommended as the diagnostic threshold for myocardial infarction, but troponin concentrations are strongly influenced by age. Our aim was to assess the diagnostic performance of cardiac troponin in older patients presenting with suspected myocardial infarction.
Elevating microglia TREM2 reduces amyloid seeding and suppresses disease-associated microglia
Authors: Na Zhao, Wenhui Qiao, Fuyao Li, Yingxue Ren, Jiaying Zheng, Yuka A. Martens, Xusheng Wang, Ling Li, Chia-Chen Liu, Kai Chen, Yiyang Zhu, Tadafumi C. Ikezu, Zonghua Li, Axel D. Meneses, Yunjung Jin, Joshua A. Knight, Yixing Chen, Ligia Bastea, Cynthia Linares, Berkiye Sonustun, Lucy Job, Madeleine L. Smith, Manling Xie, Yong U. Liu, Anthony D. Umpierre, Koichiro Haruwaka, Zachary S. Quicksall, Peter Storz, Yan W. Asmann, Long-Jun Wu, Guojun Bu
Journal: The Journal of Experimental Medicine (2022)

TREM2 is exclusively expressed by microglia in the brain and is strongly linked to the risk for Alzheimer’s disease (AD). As microglial responses modulated by TREM2 are central to AD pathogenesis, enhancing TREM2 signaling has been explored as an AD therapeutic strategy. However, the effective therapeutic window targeting TREM2 is unclear. Here, by using microglia-specific inducible mouse models overexpressing human wild-type TREM2 (TREM2-WT) or R47H risk variant (TREM2-R47H), we show that TREM2-WT expression reduces amyloid deposition and neuritic dystrophy only during the early amyloid seeding stage, whereas TREM2-R47H exacerbates amyloid burden during the middle amyloid rapid growth stage. Single-cell RNA sequencing reveals suppressed disease-associated microglia (DAM) signature and reduced DAM population upon TREM2-WT expression in the early stage, whereas upregulated antigen presentation pathway is detected with TREM2-R47H expression in the middle stage. Together, our findings highlight the dynamic effects of TREM2 in modulating AD pathogenesis and emphasize the beneficial effect of enhancing TREM2 function in the early stage of AD development.